The present invention relates to a tricyclic compound effective for inhibiting sPLA2-mediated fatty acid release.
sPLA2 (secretory phospholipase A2) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA2-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA2. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA2, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA2 is considered to be extremely wide and, besides, its action is potent.
Examples of sPLA2 inhibitors include compounds described in EP-620214 (JP Laid-Open No. 010838/95, U.S. Pat. No. 5,578,634), EP-620215 (JP Laid-Open No. 025850/95, U.S. Pat. No. 5,684,034), EP-675110 (JP Laid-Open No. 285933/95, U.S. Pat. No. 5,654,326), WO 96/03120 (JP Laid-Open No. 505336/98), WO 96/03376 (JP Laid-Open No. 503208/98, U.S. Pat. No. 5,641,800), WO 96/03383 (JP Laid-Open No. 505584/98), WO 97/21664 (EP-779271), WO 97/21716 (EP-779273), WO 98/18464 (EP839806), WO98/24437(EP846687), WO98/24756, WO98/24794, WO98/25609, WO99/51605, WO99/59999 and the like, or parabromophenacylbromide, mepacrine, manoaride, theilocien A and the like.
The object of the present invention is to provide tricyclic compounds having sPLA2-inhibitory activities and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, and cardiac infarction.
The present invention relates to I) a compound represented by the formula (I): 
wherein R1 is a group selected from (a) C1 to C20 alkyl, C2 to C20 alkenyl, C2 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, or (c) xe2x80x94(L1)xe2x80x94R5 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R5 is a group selected from the groups (a) and (b);
one of R3 and R4 is xe2x80x94(L2)-(acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5 and the other is a hydrogen atom;
A ring is a group represented by the formula: 
wherein R2 is CONH2 or CONHNH2;
R18, R19, R20, R22, and R23 are each independently a hydrogen atom, or lower alkyl;
R24 and R25 are each independently a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl;
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
In more detail, the present invention relates to II)-XIII).
II) A compound represented by the formula (II): 
wherein R24, R25, and A ring are as defined above;
R6 is xe2x80x94(CH)mxe2x80x94R9 wherein m is an integer from 1 to 6, and R9 is (d) a group represented by the formula: 
wherein a, c, e, n, q, t and v are each independently an integer from 0 to 2; R10 and R11 are each independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, optionally substituted heteroaryl and C1 to C10 haloalkyl; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are each independently an integer from 0 to 5; r is an integer from 0 to 7; and u is an integer from 0 to 4, or R9 is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, phenyl, and a halogen;
one of R7 and R8 is xe2x80x94(L3)xe2x80x94R12 wherein L3 is represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R5)xe2x80x94, or xe2x80x94Sxe2x80x94; R13 and R14 are each independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R15 is a hydrogen atom or C1 to C6 alkyl; and
R12 is represented by the formula: 
wherein R16 is hydrogen atom, a metal, or C1 to C10 alkyl; R17 is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8;
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
III) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described in I) or II), wherein said R1 and R6 are represented by the formula: 
wherein R10, R11, b, d, f, p, r, u, w, xcex1, xcex2, and xcex3 are as defined above.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may substitute at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
IV) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described in any one of I) to III), wherein said R1 and R6 are represented by the formula: 
wherein R10, R11, p, u, and w are as defined above.
When the above p, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another.
V) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described in any one of I) to IV), wherein said R3 and R7 are xe2x80x94Oxe2x80x94(CH2)mxe2x80x94COOH (m is as defined above).
VI) A compound represented by the formula (III): 
wherein R10, A ring, and m are as defined above,
its prodrug, their pharmaceutically acceptable salt, or hydrate thereof.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described in any one of I) to VI), wherein said R2 is xe2x80x94CONH2.
VIII) A compound, its prodrug, their pharmaceutically acceptable salt, or hydrate thereof as described in any one of I) to VII), wherein said R18, R19, R20, R21, R22, and R23 are hydrogen atoms.
IX) A pharmaceutical composition containing a compound as described in any one of I) to VIII) as an active ingredient.
X) A pharmaceutical composition as described in IX), which is for inhibiting sPLA2.
XI) A pharmaceutical composition as described in IX), which is for treatment or prevention of inflammatory diseases.
XII) Use of a compound of any one of I) to VII) for preparation of a pharmaceutical composition for treating inflammatory diseases.
XIII) A method for treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases, which comprises administration to said mammal of a compound as described in any one of I) to VIII) in a pharmaceutically effective amount.
In the present specification, the term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.
The term xe2x80x9calkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl); phenyl, naphthyl, norbornyl, bicycloheptadienyl, indenyl, stilbenyl, terphenylyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula: 
wherein x is an integer from 1 to 8.
The term xe2x80x9cheterocyclic groupxe2x80x9d used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated heterocyclic nucleus having 5 to 14 ring atoms and containing 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrrolyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.
Preferable are thienyl, furyl, thiazolyl, pyridyl as the heterocyclic ring group in the R10 and R11.
Preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: 
wherein v is an integer from 0 to 2; R10 and R11 are each independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, optionally substituted heterocyclic group, and C1 to C10 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
A more preferable example includes (h) a group represented by the formula: 
wherein R10, R11, xcex1, xcex2, and xcex3 are the same as defined above, and y is independently 0 or 1. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
The term xe2x80x9cnon-interfering substituentxe2x80x9d in the present specification means a group suitable for substitution of group (a) (e.g., xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d xe2x80x9ccarbocyclic groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d) in R1 on tricyclic compound represented by the formula (I). An example of the non-interfering substituents includes C1 to C10 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C10 alkyloxy, C1 to C6 alkyloxy C1 to C6 alkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C1 to C6 alkyloxy C1 to C6 alkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C1 to C6 alkylcarbonyl (such as methylcarbonyl and ethylcarbonyl), C1 to C6 alkylcarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C1 to C6 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C1 to C6 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), mono or di C1 to C6 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C10 alkylthio, C1 to C6 alkylthiocarbonyl (such as methylthiocarbonyl and ethylthiocarbonyl), C1 to C6 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C6 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to C6 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C6 haloalkylsulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C1 to C10 haloalkyl, C1 to C6 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), C1-C6 alkyloxycarbonyl (such as methyloxycarbonyl and ethyloxycarbonyl), xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C6 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), xe2x80x94(CONHSO2R20), formyl, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, xe2x80x94(CH2)zxe2x80x94COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, carbonyl, carbocyclic groups, heterocyclic groups and the like, wherein z is an integer from 1 to 8 and R20 is C1 to C6 alkyl or aryl.
Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the xe2x80x9cnon-interfering substituentxe2x80x9d in the R1. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.
The term xe2x80x9chalogenxe2x80x9d in the present specification means fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ccycloalkylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.
In the present specification, an example of xe2x80x9calkyloxyxe2x80x9d includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.
In the present specification, an example of xe2x80x9calkylthioxe2x80x9d includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.
The term xe2x80x9cacidic groupxe2x80x9d in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a tricyclic nucleus through a suitable linking atom (hereinafter defined as xe2x80x9cacid linkerxe2x80x9d). An example of the acidic group includes (k) a group represented by the formula: 
wherein R16 is a hydrogen atom, a metal, or C1 to C10 alkyl; each R17 is independently a hydrogen atom or C1 to C10 alkyl; h is an integer from 1 to 8. Preferable is (1) xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2. More preferable is (m) xe2x80x94COOH. And preferable is also their ester and prodrug.
The term xe2x80x9cacid linkerxe2x80x9d in the present specification means a divalent linking group represented by a symbol xe2x80x94(L2)xe2x80x94, and it functions to join tricyclic nucleus to an xe2x80x9cacidic groupxe2x80x9d in the general relationship. An example of it includes (n) a group represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R15)xe2x80x94, or xe2x80x94Sxe2x80x94, and R13 and R14 are each independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or halogens, wherein R15 is a hydrogen atom or C1-C6 alkyl. Preferable are (o) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R15)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R15 is C1 to C6 alkyl and Ph is phenyl. More preferable is (p) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94CH2xe2x80x94.
In the present specification, the term xe2x80x9cacid linker lengthxe2x80x9d means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group xe2x80x94(L2)xe2x80x94 which connects tricyclic nucleus with the xe2x80x9cacidic groupxe2x80x9d. The presence of a carbocyclic ring in xe2x80x94(L2)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of xe2x80x94(L2)xe2x80x94. A preferable length is 2 to 3.
The term xe2x80x9chaloalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with the aforementioned xe2x80x9chalogenxe2x80x9d at arbitrary position(s). An example of the haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with hydroxy,at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.
In the present specification, the term xe2x80x9chaloalkylxe2x80x9d in xe2x80x9chaloalkyloxyxe2x80x9d is the same as defined above. An example of it includes 2-chloroethyloxy, 2-trifluoroethyloxy, 2-chloroethyloxy and the like.
The term xe2x80x9carylxe2x80x9d in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1-naphthyl are preferred.
The term xe2x80x9caralkylxe2x80x9d in the present specification means a group wherein the aforementioned xe2x80x9calkylxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. Such aryl may have a bond at any substitutable position. An example of it includes benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as 1-naphtbylmethyl) and the like.
The term xe2x80x9calkyloxycarbonylxe2x80x9d in the present specification means C1-C6 alkyloxycarbonyl. An example of the alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.
The term xe2x80x9cacylxe2x80x9d in the present specification means C1-C6 alkylcarbonyl or arylcarbonyl opptionally substituted with a halogen and the like. An example of the acyl includes acetyl, trifluoroacetyl, propionyl, benzoyl and the like.
In the present specification, preferable are a halogen, C1-C10 alkyl, C1-C10 alkyloxy, C1-C10 alkylthio, and C1-C10 haloalkyl and the like as substituents for xe2x80x9coptionally substituted phenylxe2x80x9d andxe2x80x9d xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d. These substituents may be substituted with one or more positions.
A group of preferable substituents as the R1 to R3 of the compound represented by the formula (I) will be shown in items (A) to (O). Preferable are hydrogen atoms as the R4, R18, R19, R20, R21, R22, R23, R24, and R25. Items (f) to (p) are the same group as described above.
As the R1, (A): xe2x80x94(L1)xe2x80x94R5, (B): xe2x80x94(CH2)1-2-(f), (C): xe2x80x94(CH2)1-2-(g), and (D): xe2x80x94(CH2)1-2-(h) are preferred.
As the R2, (E): CONH2 or CONHNH2, and (F): CONH2 are preferred.
As the R3, (G): -(n)-(k), (H): -(n)-(l), (I): -(n)-(m), (J): -(o)-(k), (K): -(o)-(l), (L): -(o)-(m), (M): -(p)-(k), (N): -(p)-(l), and (O): -(p)-(m) are preferred.
A preferred group of compounds represented by the formula (I) is shown below.
(R1,R2,R3)=(A,E,G), (A,E,H), (A,E,I), (A,E,J), (A,E,K), (A,E,L), (A,E,M), (A,E,N), (A,E,O), (A,F,G), (A,F,H), (A,F,I), (A,F,J), (A,F,K), (A,F,L), (A,F,M), (A,F,N), (A,F,O), (B,E,G), (B,E,H), (B,E,I), (B,E,J), (B,E,K), (B,E,L), (B,E,M), (B,E,N), (B,E,O), (B,F,G), (B,F,H), (B,F,I), (B,F,J), (B,F,K), (B,F,L), (B,F,M), (B,F,N), (B,F,O), (C,E,G), (C,E,H), (C,E,I), (C,E,J), (C,E,K), (C,E,L), (C,E,M), (C,E,N), (C,E,O), (C,F,G), (C,F,H), (C,F,I), (C,F,J), (C,F,K), (C,F,L), (C,F,M), (C,F,N), (C,F,O), (D,E,G), (D,E,H), (D,E,I), (D,E,J), (D,E,K), (D,E,L), (D,E,M), (D,E,N), (D,E,O), (D,F,G), (D,F,H), (D,F,I), (D,F,J), (D,F,K), (D,F,L), (D,F,M), (D,F,N), and (D,F,O).
The compounds of the invention represented by the formula (I) can be synthesized in accordance with well-known method described in chemical journals. The compounds of the invention represented by the formula (I) can also be synthesized in accordance with the following methods A to E. Although representative methods are exemplified, enlarged rings can also be synthesized in a similar manner. 
wherein R1, R3, R4, R5, R18, R19, R20, R21, R24, and R25 are as defined above, R26 is lower alkyl, R27COxe2x80x94 is a precursor of R1, R28 is optionally substituted aryl, Hal are independently a halogen.
(Process 1)
A mixture of the compound (IV) and the compound (V) is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50 to 70xc2x0 C. for 3 to 36 h, preferably 12 to 24 h to give the quaternary salt. To a solution of the obtained quaternary salt in a solvent such as 1,2-dichloroethane or acetonitrile is added a base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or triethylamine, and the resulting mixture is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50 to 70xc2x0 C. for 3 to 36 h, preferably 12 to 24 h. After the reaction mixture is subjected to a usual work-up, the compound (VII) can be obtained.
The compound (IV) is commercial available or can be synthesized in accordance with the method described in J. Med. Chem., 3636-58(1996). The compound (V) can be synthesized in accordance with the method described in Synth. Commun. 24, 2557 (1994).
(Process 2)
The present process is performed by Friedel-Crafts reaction. To a solution of the compound (VI) in a solvent such as 1,2-dichloroethane or dichloromethane are slowly added R27COHal and a Lewis acid such as AlCl3, SbF5, or BF3 at xe2x88x9278xc2x0 C. to 10xc2x0 C., preferably xe2x88x9220xc2x0 C. to ice bath, and the reaction mixture is stirred at xe2x88x9210xc2x0 C. to 10xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C. for 5 to 30 min, preferably 10 to 20 min. This reaction can be performed without solvent by dissolving the compound (VI) in R27COHal and in accordance with the above-mentioned procedure. After the reaction mixture is subjected to a usual work-up, the compound (VII) can be obtained (Ref: J. Med. Chem., 39, 3636-58(1996)).
(Process 3)
The present process includes the reduction of an ester group of a side chain at 2-position and a carbonyl group of 3-position at the same time. To a solution of the compound (VII) in a solvent such as tetrahydrofuran or dichloromethane are added a reducing agent (e.g., a mixed agent of sodium borohydride and a Lewis acid such as aluminum chloride), and the mixture is reacted at 20xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 50xc2x0 C. for 1 to 5 h, preferably 1 to 3 h to obtain the compound (VIII).
(Process 4)
To a solution of the compound (VIII) in a solvent such as 1,2-dichloroethane or tetrahydrofuran are added Halxe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94Hal (e.g., oxalyl chloride) and a base such as N-methylmorpholine or triethylamine, and the mixture is stirred at 30 to 70xc2x0 C., preferably 40 to 60xc2x0 C. for 1 to 10 h, preferably, 3 to 6 h. The reaction mixture is poured into a cold aqueous ammonium solution and the resulting mixture is stirred for 5 to 30 min, preferably, 10 to 20 min. After the reaction mixture is subjected to a usual work-up, the compound (IX) can be obtained.
(Process 5)
The present process includes the conversion of a hydroxy group to halogen. To a solution of the compound (IX) is added triphenylphosphine and N-bromosuccinimide, and the mixture is reacted at 0xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 1 to 10 h, preferably for 1 to 5 h to obtain the compound (X). It can be synthesized by using phosphorous tribroimde in accordance with the method described in Org. Synth Coll. Vol. 2, p-358, or by using triphenylphosphine and bromine in accordance with the method described in J. Am. Chem. Soc., 107, 5238 (1995).
(Process 6)
The present process includes the preparation of the phosphonium salt. A mixture of the compound (X) and triphenylphosphine in a solvent such as acetonitrile or toluene is reacted at 80 to 150xc2x0 C., preferably 100 to 120xc2x0 C. for 5 to 72 h, preferably 10 to 24 h to obtain the compound (XI).
(Process 7)
The present process is for constructing a ring by Wittig reaction. To a solution of the compound (XI) in a solvent such as acetonitrile, or tetrahydrofuran is added a base such as 1,8-dizabicyclo[5.4.0]-7-undecene (DBU), potassium t-butoxide, and the mixture is reacted at 20xc2x0 C. to 120xc2x0 C., preferably 80xc2x0 C. to 100xc2x0 C. for 3 to 24 h, preferably 5 to 10 h to obtain the compound (XII).
(Process 8)
The present process includes the reduction of the double bond by hydrogenation. To a solution of the compound (XII) in a solvent such as tetrahydrofuran, methanol or ethyl acetate is added a catalyst such as Palladium-Carbon, and the mixture is reacted under hydrogen atmosphere at room temperature for 1 to 5h, preferably 1 to 2 h to yield the compound (XIII). 
wherein R1, R3, R4, R5, R18, R19, R24, R25, R26, R27, and Hal are as defined above. R29 is a methanesulfonyl group, p-toluenesulfonyl or the like.
(Process 1)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 1.
(Process 2)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 2.
(Process 3)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 3.
(Process 4)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 4.
(Process 5)
The present process is for the conversion of a hydroxy group at 2-position to a good leaving group followed by the reduction of a carbonyl group of a side chain at 1-position. A solution of the compound (XVIII) in a solvent such as dichloromethane or the like is reacted with R29xe2x80x94Cl in the presence of a base such as triethylamine or the like at 0xc2x0 C. to 80xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 1 to 5 h, preferably 1 to 2 h. A solution of the obtained compound in a solvent such as tetrahydrofuran is reacted with a reductant such as sodium borohydride at 0xc2x0 C. to 80xc2x0 C., preferably 0xc2x0 C. to 20xc2x0 C. for 1 to 5 h, preferably 1 to 2 h to give the compound (XIX).
(Process 6)
The present step is for constructing a ring. To a solution of the compound (XIX) in a solvent such as tetrahydrofuran, or dimethylformamide is added a base such as sodium hydride, or potassium tert-butoxide at 0 to 100xc2x0 C., preferably 20 to 50xc2x0 C. for 1 to 8 h, preferably 1 to 3 h to give the compound (XX). 
wherein R1, R3, R4, R5, R18, R19R20, R21, R24, R25, R27, and Hal are as defined above, one of R30 and R31 is a hydrogen atom, the other is a protecting group of an amino group.
(Process 1)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 1.
(Process 2)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 2.
(Process 3)
The present process is for the reduction of a carbonyl group at 3-position methylene. To a solution of Lewis acid (e.g., AlCl3 or the like) in a solvent such as dichloromethane or tetrahydrofuran is slowly added a reducing agent such as borane-tert-butylamine complex or sodium borohydride at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably in an ice bath, and the reaction mixture is stirred for 5 to 30 min, preferably 10 to 20 min. To the resulting reaction mixture is added a solution of the compound (XXIII) in a solvent such as dichloromethane or tetrahydrofuran at xe2x88x9220xc2x0 C. to 10xc2x0 C. preferably in an ice bath and the mixture is stirred for 20 to 30 min, and then at 15xc2x0 C. to 40xc2x0 C., preferably 20 to 30xc2x0 C. for 1 to 5 h, preferably 2 to 3 h. After a usual work-up, the compound (XXIV) can be obtained (Ref: J. Med. Chem., 39, 3636-58 (1996)).
(Process 4)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 4.
(Process 5)
The present process is for the deprotection of the protecting group of an amino group and the construction of the ring. To a solution of the compound (XXV) in a solvent such as dichloromethane or the like is added an acid such as trifluoroacetic acid and the mixture is reacted at 0xc2x0 C. to 80xc2x0 C., preferably 20xc2x0 C. to 50xc2x0 C. for 1 to 20 h, preferably 3 to 8 h to give the compound (XXVI). 
wherein R1, R3, R4, R24, R25, R27, and Hal are as defined above, R32 is lower alkyl.
(Process 1)
The present process is for hydrolysis of ester. The compound (XXVII) can be synthesized in accordance with the method described in J. Org. Chem., 36, 813 (1971). To a solution of the compound (XXVII) in a solvent such as tetrahydrofuran, ethanol, or dimethylsulfoxide is added a base such as sodium hydroxide, potassium hydroxide at 20 to 150xc2x0 C., preferably 50 to 150xc2x0 C. for 1 to 10 h, preferably 3 to 5 h to obtain the compound (XXVIII).
(Process 2)
The present process is for the decarboxylation. A solution of the compound (XXVIII) in solvent such as dimethyl sulfoxide or dimethylformamide is reacted at 50 to 200xc2x0 C., preferably 100 to 150xc2x0 C. for 1 to 5 h, preferably 1 to 2 h.
(Process 3)
The present process may be carried out in accordance with the same procedure as that of the Method Cxe2x80x94Process 3.
(Process 4)
The present process is the reduction of carboxylic acid. Diborane, sodium borohydride-aluminum chloride, diisobutylaluminum hydride, lithium aluminum hydride and the like can be used as a reducing agent. In case of using lithium aluminum hydride, to a solution of the compound (XXX) in tetrahydrofuran or diethyl ether is added lithium aluminum hydride at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 50xc2x0 C. for 1 to 5 h, preferably 1 to 2 to give the compound (XXXI).
(Process 5)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 4.
(Process 6)
The present process is for the oxidation of a hydroxy group and the construction of the pyridazine ring.
The present process can be performed by usual oxidation and the following four types of oxidation are preferable.
i) PCC Oxidation (To a solution of the compound (XXXII) in a solvent such as dichloromethane or the like is added pyridinium chlorochromate (PCC) and the mixture is reacted at xe2x88x9220 to 60xc2x0 C., preferably 0 to 40xc2x0 C. for 1 to 30 h, preferably 3 to 20 h to yield the aimed oxidant.)(Ref: Tetrahedron Lett., 2647-2650 (1975))
ii) Swern Oxidation (Dichloromethane is cooled at xe2x88x9278xc2x0 C., and to the solution are added successively oxalyl chloride, dimethyl sulfoxide, and the compound (XXXII). The mixture is warmed to xe2x88x9245xc2x0 C. to 0xc2x0 C., and reacted for 1 to 30 h, preferably 1 to 10 h and then is subjected to usual work-up to give the desired compound.) (Ref: J. Org. Chem., 43, 2480-2482 (1978))
iii) Dess-Martin Oxidation (The oxidation can be carried out in solution such as tetrahydrofuran or the like by reacting Dess-Martin reagent in dimethyl sulfoxide.) (Ref: J. Org. Chem., 48, 4155-4156 (1983))
iv) Oxidation with a halogeno oxoacid (The compound (XXXII) is reacted in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) with an oxidizing agent such as a halogeno oxoacid or the like in accordance with the method described in J. Org. Chem., 52, 2559-2562 (1987) to give the product. 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl or like the can be used as TEMPO or the like. Sodium hypochlorite, sodium hypobromite, sodium bromite, high test hypochlorite or the like can be used as a halogeno oxoacid. Ethyl acetate, acetonitrile, and dichlormethane can be used as a solvent.
Ring closing reaction can be carried out by reacting the obtained compound with hydrazine hydrate (NH2NH2H2O) in a solvent such as ethanol or the like at 0xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 1 to 10 h, preferably 2 to 3 h.) 
wherein R1, R3, R4, R24, and R25 are as defined above.
(Process 1)
The present process is for the preparation of N-alkoxyphthalimide by Mitsunobu-reaction. The compound (XXXII) in a solvent such as tetrahydrofuran or the like is reacted with triphenylphosphine, N-hydroxyphthalimide, diethyl azodicarboxylate, and the like at 0 to 80xc2x0 C., preferably 10 to 30xc2x0 C. for 1 to 5 h, preferably 1 to 2 h to obtain the compound (XXXIV).
(Process 2)
The present process is for the ring formation. The compound (XXXIV) in a solvent such as dichloromethane or the like is reacted with reagents such as hydrazine, N-methylhydrazine or the like at 0xc2x0 C. to 80xc2x0 C., preferably 10xc2x0 C. to 30xc2x0 C. for 1 to 5 h, preferably 1 to 2 h to give the compound (XXXV).
Where a compound of the present invention has an acidic or basic functional group, a variety of salts having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Addition salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d. (e.g., S. M. Berge et al., xe2x80x9cPharmaceutical Salts, xe2x80x9cJ. Phar. Sci., 66, 1-19 (1977)). Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edicirates, estrates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialsanyrates, hexylresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates, manderates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates, nitrates, oleates, oxarates, palmitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates, sucinates, tanates, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.
In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoisomers, and thereafter separating the mixture in accordance with a well-known manner.
Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. More preferable is C1-C6 alkyl ester of acidic group (e.g., methyl ester, ethyl ester). Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.
The term xe2x80x9cinhibitxe2x80x9d means that release of fatty acid started by sPLA2 decreases significantly by the compounds:of the present invention from viewpoint of prevention and treatment of disease. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.
The compounds of the present invention exhibit sPLA2 inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), and (III), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their hydrate is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, cardiac infarction.
The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.
In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.
Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.
In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.
The dosage varies with the conditions of the disease, administration route, age and body weight of patient. In the case of oral administration, the dosage can generally be between 0.01 to 50 mg/kg/day for adult.